1. Field of the Invention
This invention relates to transmucosal drug delivery systems. In another aspect this invention relates to drug delivery systems containing a heparinic anticoagulant, such as a heparin or a heparin fragment.
2. Description of the Related Art
Transmucosal drug delivery systems are designed to deliver a therapeutically effective amount of drug across a mucosal surface, typically the oral mucosa, of a patient. Delivery of drugs across the oral mucosa avoids hepatic first-pass inactivation, poor or erratic absorption from the gastro-intestinal tract, inactivation by gastro-intestinal fluids, and other modes of inactivation characteristic of oral drug ingestion. Sustained release adhesive bandages, patches, and the like that contain drugs are known to the art.
Patent Application WO 90/06505 (Scholz et al.) discloses a bioadhesive composition comprising drug and a particulate polymeric resin dispersed in a hydrophobic elastomeric component. CARBOPOL.TM. resins are among the polymeric resins said to be suitable and the hydrophobic resin can be a mixture of VISTANEX.TM. L100 polyisobutylene and VISTANEX LMMH polyisobutylene.
Heparin is an anionic polysaccharide of mammalian origin having anticoagulant properties. It is a heterogeneous mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids. The molecular weight ranges from 6,000 to 30,000 daltons. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acid protons of the sulfate units are partially replaced by sodium ions. Heparin is biosynthesized and stored in mast cells of various animal tissues, particularly liver, lung or gut. Commercial heparin is isolated from beef lung or pork intestinal mucosa. Heparin is given parenterally for the treatment and prophylaxis of thrombo-embolic disorders and as an adjunct to thrombolytic therapy.
Low molecular weight (1500-8000 daltons) heparins are fragments of heparin with anticoagulant activity. They can be obtained by chemical or enzymatic depolymerization of standard heparin. Commercially available low molecular weight heparins differ in their method of production, molecular weight range, chain end groups and degree of sulfation. Like heparin, these compounds inhibit the action of antithrombin III but they are characterized by a higher ratio of anti-factor-Xa to anti-thrombin activity than heparin. Low molecular weight heparins have less effect on platelet aggregation than heparin. They are used in the treatment and prophylaxis of venous thromboembolism. Therapy may be monitored by measurement of plasma anti-factor-Xa activity.
Dalteparin sodium is prepared by the nitrous acid degradation of heparin obtained from the intestinal mucosa of pigs. The majority of the components have a 6-O-sulpho-2,5-anhydro-D-mannitol structure at the reducing end of the chain. The molecular weight of 90% of the components is between 2000 and 9000 daltons and the average molecular weight is about 5000 daltons. The sulfur content is about 11%.
Enoxaparin sodium is prepared by alkaline degradation of heparin benzyl ester obtained from the intestinal mucosa of pigs. The majority of the components have a 2-O-sulfo-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain. The molecular weight ranges between 3500 and 5500 daltons and the average molecular weight is about 4500 daltons. The degree of sulfation is about 2 per disaccharide unit.
Nadroparin calcium is prepared by nitrous acid degradation of heparin obtained from the intestinal mucosa of pigs. The majority of the components have a 2-O-sulpho-.alpha.-L-idopyranosuronic acid structure at the non-reducing end of the chain and a 6-O-sulpho-2,5-anhydro-D-mannitol structure at the reducing end of the chain. The average molecular weight is about 4500 daltons. The degree of sulfation is about 2.1 per disaccharide unit.
Parnaparin sodium is prepared by hydrogen peroxide and copper(II)acetate degradation of heparin obtained from the intestinal mucosa of pigs. The majority of the components have a 2-N,6-O-sulpho-2,5-D-glucosamine structure at the reducing end of the chain. The molecular weight ranges between 4000 and 5000 daltons. The degree of sulfation is about 2.15 per disaccharide unit.
Reviparin sodium is prepared by nitrous acid degradation of heparin obtained from the intestinal mucosa of pigs. The majority of the components have a 2-O-sulpho-.alpha.-L-idopyranosuronic acid structure at the non-reducing end of the chain and a 2-N,6-O-disulpho-D-mannitol structure at the reducing end of the chain. The molecular weight of 90% of the components is between 2000 and 8000 daltons and the average molecular weight is 3500 to 4500 daltons. The degree of sulfation is about 2.2 per disaccharide unit.
Tinzaparin sodium is prepared by enzymatic degradation of the intestinal mucosa of pigs. The majority of the components have a 2-O-sulpho-4-enopyranosuronic acid structure at the non-reducing end of the chain and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain. The molecular weight of 70% of the components is between 1500 and 10,000 daltons and the average molecular weight is about 4500 daltons. The degree of sulfation is 2.0 to 2.5 per disaccharide unit.